The purpose of this Notice is to inform potential applications to the National Institute on Drug Abuse (NIDA) and National Institute on Aging (NIA) of special interest in grant applications to conduct rigorous research on cannabis and potentially addictive, psychoactive prescription drug use (specifically opioids and benzodiazepine) in older adults. This program will focus on two distinct older adult populations (over the age of 50): (1) individuals with earlier use onset of cannabis and the specified drug classes who are now entering older age, or (2) individuals who initiate use of cannabis and the specified drug classes after the age of 50. Insights gained from this initiative have the potential to inform the public and health care systems regarding use of cannabis and prescription opioids and benzodiazepines in older populations.

Background

Compared with younger adults, adults over the age of 50 represent the largest consumers of prescription medications, and individuals in this age group are three times more likely to be prescribed opioids and benzodiazepines. Individuals over 50 report using these prescription drugs to alleviate pain, sleep disorders/insomnia, and anxiety. Opioid and benzodiazepine use by older adults is associated with increased incidence of falls, respiratory failure, sedation, confusion, and cognitive impairments. Prescription drug use patterns during older age are especially problematic for women as they are prescribed these drugs more often, consume them in larger quantities, and use them for longer durations of time. In fact, from 1999 to 2007, overdose deaths in women grew 500% among those aged 55 64 years. These prescribing practices in older patients can be problematic and may pose a severe health risk. A recent one-year retrospective study revealed that a third of participants over the age of 60 were using at least one potentially inappropriate medication, defined as medications with risks that outweigh the potential benefits of the drug. Since prescription drugs will continue to be incorporated into health care plans for individuals over 50, more information is needed to characterize the health outcomes associated with opioid and benzodiazepine prescription drug use in older adults.

Evolving medical and recreational cannabis legalization have transformed the availability of cannabis in states impacted by these policies. To date, 33 states and the District of Columbia have legalized cannabis use for medicinal purposes and 6 additional states have approved the use of CBD oil. While the list of approved medical conditions for medical cannabis use vary across states, medical cannabis use for pain management remains consistent across states. In a nationwide survey, approximately 50-70% of older adults endorse pain symptoms and 19 million Americans report pain in the last month. Interestingly, patient expenditures for prescription drugs under the Medicare Part D Plan dropped in states with legalized medical cannabis use, suggesting that individuals are substituting prescription medications for cannabis. This emerging trend suggests that older adults may be substituting prescription drugs with cannabis. With recent shifts in cannabis legalization policy, there is potential for cannabis consumption to increase across all age groups, including adults over the age of 50. However, compared to adolescents and young adults, the health consequences stemming from cannabis use are currently unknown for older adults.

Increased drug use among older adults can be complicated by other normal changes that occur during healthy aging. For example, drug metabolism rate decreases with age, which may lead to unintended outcomes and other adverse health consequences. Of particular relevance , the brain also undergoes significant neuroadaptations during aging. After the age of 40, the brain loses approximately 5% of its volume per decade, with some data suggesting an accelerated rate of volume loss at the age of 70. Reduced brain volume predominately occurs in the temporal lobes, cerebellum, hippocampus, and prefrontal cortex. Within these brain regions, cellular and molecular data indicate alterations in dendritic branching and reductions in the number of axodendritic synapses. Post-mortem brain analyses reveal decreased D1 and D2 receptor expression, reduced dopamine synthesis, and diminished receptor and dopamine transporter binding during older age. Additionally, age-related alterations in serotonin and acetylcholine release and neurotransmitter receptor expression have also been observed in adults over the age of 50. The aging-related changes seen in these brain regions are important, given their roles in cognitive function, decision-making, reward processing, and emotional regulation, which all have significant implications for daily life. Currently, there is a lack of knowledge on how cannabis, opioids, or benzodiazepines impact these changing brain systems and their associated behavioral and psychological processes during aging.

Epidemiological and Health Services Research Priorities include:

• The long term consequences (i.e., 3-6 months) of cannabis substitution on prescription drug use
• The associated health care utilization and costs with cannabis substitution (hospitalization, treatment services utilization, overdose, etc)
• Health care provider attitudes towards cannabis substitution, stratified by state legalization status (recreational, medical only, complete prohibition)
• Predictive analytics supporting treatment response to cannabis substitution on substance use disorder, chronic pain management, and health care utilization
• Cannabis use characteristics (route of administration, associated medical condition)
• Novel treatment and prevention interventions to address high-risk populations (e.g., women, individuals with comorbidities)
• Research to elucidate the biological, behavioral, social, geographical, and health system-related causes and consequences of drug abuse, including studies of cohort and individual differences in drug abuse in later life
• Medical conditions reported for cannabis use
• Health outcomes in substance users or previously drug-na ve users with or without HIV

Clinical/Basic Science Research Priorities include:

Examples of research topics to be executed in older adults or age appropriate animal models include, but are not limited to:

• Contribution of drug use during aging to the development of substance abuse or dependence and the associated vulnerability/resilience factors, including sex differences
• Changes in cognition, motivation, affect, emotion regulation, and self-regulation (e.g., sleep, physical activity, adherence to medications) associated with cannabis and prescription drug use
• Impact of prior drug use on the emergence of age-related cognitive and behavioral deficits (e.g., memory, attention, self-regulatory processes, social behavior, driving performance, balance, mobility)
• Efficacy of behavioral and pharmacological treatment approaches for substance use disorders in older individuals
• Aging-relevant characterization of physiological symptoms associated with substance use disorder (e.g., tolerance, withdrawal, etc.)
• Aging-related changes in responsivity to delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), or other phytocannabinoids, opioids and benzodiazepines across all levels of analysis (behavior, neurobiology, epi/genetics, physiology)
• Consequences of aging on metabolic and physiological changes related to cannabis use (THC or CBD)
• Functional neurobiological consequences following cannabis and/or prescription drug use (e.g., neurochemical changes, neural plasticity, receptor density, circuitry or connectivity, impact on neurogenesis, etc.)
• Neuroimmune and neuroinflammatory effects related to cannabis or prescription drug use

Application and Submission Information

This notice applies to due dates on or after June 5, 2020 and subsequent receipt dates through September 8, 2023.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

PA-19-055 - NIH Research Project Grant (Parent R01 Clinical Trial Required)

PA-19-056 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-19-091 NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

PA-19-052: NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)

PA-19-092: NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)

PA-19-053: NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-19-054: NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-DA-20-014 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be not be considered for the NOSI initiative.

Please direct all inquiries to the Scientific/Research, Peer Review, and Financial/Grants Management contacts in Section VII of the listed funding opportunity announcements.

Scientific/Research Contact(s)

Shelley Su, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-402-3869
Email: shelley.su@nih.gov

Devon Oskvig, PhD
National Institute on Aging (NIA)
Telephone: 301-827-5899
Email: devon.oskvig@nih.gov